Cardiovascular (CVD) and metabolic (MetS) diseases constitute a major public-health burden and, therefore, understanding the genetic basis of these traits is very important. The recent Genome-Wide Association Studies (GWAS) made good progress, but not enough. For example, two large consortia (CHARGE and ICBP) identified 13 loci for blood pressure (BP) which collectively explain less than 2% of BP variance (with most of the heritability still "missing"). The near-exclusive reliance on main effects of single genetic markers has been one of the major barriers to identifying more of the genes underlying these disease traits. Against this background, Gene-Environment Interaction (GEI) methods are known to vastly increase the statistical power for gene discovery (preliminary studies). Also, analysis of longitudinal data can be much more powerful than that of cross-sectional data. Combining GEI and longitudinal data should yield even more power. Despite the knowledge that GEI and longitudinal data both vastly improve the statistical power for gene discovery, this knowledge has not been leveraged yet, thus missing an opportunity to find (hopefully many) novel disease loci from large volumes of existing GWAS data. Thusly motivated, we propose to harness the large existing longitudinal Framingham Heart Study (FHS) data using our GEI methods including gene-age, gene-sex, gene-obesity, and gene-lifestyle interactions. This study will use FHS data on the 7 visits of the 'Offspring Cohort', the corresponding 7 visits of the 'Original Cohort', and the 'Generation 3 Cohort'(G3), to a total of 9,168 discovery subjects with GWAS data. Data include GWAS data, cardiovascular and metabolic phenotypes, and lifestyle data on physical activity, alcohol consumption, smoking, and socio-economic status (SES) in 2 to 3 generation families. All significant results will be replicated in four external studies involving 22,824 replication subjects. Completion of this project has the potential to discover (hopefully many) novel disease loci, which could effectively motivate others to re-analyze large volumes of existing GWAS data using GEI methods, ultimately leading to new diagnostic tools and therapeutic interventions. PUBLIC HEALTH RELEVANCE: The primary goal of the proposed research is to exploit large existing genome-wide association study (GWAS) data using gene-environment interaction (GEI) methods to discover (hopefully many) more genetic loci for cardiovascular and metabolic disease traits. The investigation will be carried out in a large existing longitudinal Framingham Heart Study with 9,168 subjects and 4 external replication studies with 22,824 subjects.